Cells often aren’t randomly distributed in a tissue, but are aligned into precise configurations that give each cell a specific shape and orientation. This organization allows for proper communication among the many individual cells, so that together they can behave as one tissue. In any normal tissue, a certain amount of variation in this organization is acceptable. However, when the organization becomes significantly disrupted in cases of disease, the cells in a tissue fail to function together and the results are catastrophic. Johns Hopkins researchers are using tightly integrated math and experiments to predict how cells will behave when their organization changes. The researchers then use mathematical predictions to create different patterns of brain and heart cells by printing proteins on the surface of a glass slide to create a specific pattern that cells stick to. The behavior of the cells in the new pattern is analyzed and compared to the original mathematical prediction. “We wanted to see if we could use the geometry of the cells to control how the cells function,” says Andre Levchenko, Ph.D., associate professor of biomedical engineering in the Institute for Basic Biomedical Sciences. Both cell types send electrical currents across tissue, either as a heart beat or a nerve impulse. “We would like to be able to compare healthy hearts or brains with abnormal tissues and develop statistical models to predict how gradual disordering of the tissue can make what is normal into what is abnormal to use as a predictive measure for health,” says Levchenko. Another practical application for this technique would be to monitor the functionality of engineered tissues before they are implanted into patients.

Tissues grow to form specific shapes, like the lobes of the liver or the long tube of the small intestine. But, little is known about how this process happens. Studying fruit fly ovaries, researchers at Johns Hopkins have discovered a way that sheets of cells in an organ can periodically squeeze to control its shape as it grows. The researchers labeled a component of the cell’s internal skeleton with a fluorescent red tag. When they looked at the red-labeled protein under a microscope, it seemed to be “flashing,” in that the color would get more intense and then disappear over six minutes or so. The researchers discovered that this protein was applying periodic squeezes to the egg chamber by contracting the cytoskeleton, and over time, this was helping to elongate the egg chamber. “If you squeeze a ball of dough in your fist, it elongates,” says Denise Montell, director of the Center for Cell Dynamics and professor of biological chemistry at Johns Hopkins. “To visualize what is happening, imagine that the egg chamber is like a ball of dough and your hand is like the cytoskeleton that contracts to make the egg chamber longer. We think this process was undiscovered previously, because not only did it need to be observed over time in living tissues, which isn’t always easy to do, but also it is difficult to get a view of all of the cells at once in a three-dimensional organ. Because of the small size of the fruit fly egg chamber, we were able to observe the coordination between a number of cells working together towards the goal of providing a force to change organ shape.”

Of special note: Graduate student Li He won the 2010 Celldance still image contest and received complementary ASCB meeting registration and a cash award.

Several years ago, researchers developed a technology that takes adult cells, like skin or blood cells, and turns them back into induced pluripotent stem (iPS) cells. Mounting evidence has suggested that these cells aren’t as flexible as once imagined because they seem to retain some of the features of their original cell type. “If a blood cell is turned into a stem cell, the genetic makeup remembers that it was once a blood cell,” says Andy Feinberg, M.D., M.P.H., director for the Center for Epigenetics at the Johns Hopkins School of Medicine. “This could make it more difficult to change the iPS cell into a cell other than a blood cell. This may limit the therapeutic potential that these cells were thought to harness, but it may also be an advantage in other cases.” The memory that the iPS cells retain is not through actual changes in the letters of the genetic code, but through an epigenetic (meaning outside of the genetic code) chemical modification called methylation, in which methyl groups are attached to the DNA.

George Daley’s group at Harvard Medical School has determined that iPS cells have a restricted ability to differentiate into blood cell, if they were not derived from blood cells originally. Collaborating with his group, Akiko Doi, a graduate student in Feinberg’s lab, found that different types of cells have specific patterns of methylation that form a sort of memory or fingerprint for that cell type. “Specific sites of DNA methylation are not wiped clean during the conversion to iPS cells and the reprogramming seems to be incomplete,” says Doi. The cell’s memory also plays an important role in disease. Certain mistakes in the cell’s memory may be harmful, says Feinberg. “Basically, if a blood cell acquires a false memory of a different cell type like a liver cell by abnormal changes in epigenetic modifications,” he says, “then it might lead to an abnormal or disease state.”